Nature Communications features Tong’s research on reducing diabetic hyperglycemia
Recent research from the lab of Qingchun Tong, PhD, professor and Cullen Chair in Molecular Medicine at The Brown Foundation Institute of Molecular Medicine, has been published in Nature Communications.
The paper titled “A neural basis for brain leptin action on reducing type 1 diabetic hyperglycemia,” shows that leptin receptor (LepR)-expressing neurons in arcuate (LepRArc), which are selectively activated in type 1 diabetes (T1D), can be inhibited in order to reduce hyperglycemia in type 1 diabetic conditions.
Uncontrolled hyperglycemia is a major issue for patients with T1D, a condition with currently just one treatment — insulin delivery. However, insulin delivery can also bring about obesity development and life-threating hypoglycemia, or abnormally low blood sugar.
“Insulin deficiency is the cause of type 1 diabetes (T1D), however accumulating evidence suggests an involvement of brain dysfunction in T1D pathogenesis,” the authors said. “T1D models exhibit severe reduction of leptin levels, suggesting a physiologic contribution of leptin loss towards uncontrolled hyperglycemia in T1D.”
Using a streptozotocin-induced diabetic mouse model (STZ), the lab discovered that LepRArc neurons in preclinical models with severe hyperglycemia and insulin deficiency, exhibited greatly-increased expression of c-Fos, a well-established indicator of neuronal activation. Following an infusion of leptin, the c-Fos expression reduced significantly, suggesting the leptin effectively inhibited the neurons.
“In addition, we also observed similar increases in c-Fos and responses to leptin treatment in another, non-obesity diabetic (NOD) model, suggesting that Arc neuron activation and its reversal by leptin represent a common feature of T1D,” the authors said. “Interestingly, we noticed that fasting-induced c-Fos expression in the Arc was also significantly colocalized with LepR neurons, compared to control fed conditions.
“Strikingly, leptin administration reduced fasting-induced c-Fos expression in a similar fashion to T1D. Given low leptin as a common feature of both fasting and T1D, these results suggest that LepRArc neuron activation is due to reduced leptin action.”
From there, the lab tested the effect of leptin infusion on fasting related counter-regulatory hormones and found that leptin effectively reduced counter-regulatory hormone levels, which are known to be greatly increased in T1D and fasting conditions.
“Thus, T1D and fasting share a common mechanism in which heightened activation of LepRArc neurons owing to reduced leptin action causes augmented counter-regulatory responses,” the authors said.
Ultimately, the lab’s data shows that leptin, similar to the effects of fasting, results in a reduction of the heightened activity of LepRArc neurons, while also reversing the activation of AMP-kinase (AMPK), a key energy sensor in neurons. Additional evidence presented suggests the leptin effect on neuron inhibition was mediated through restoring nutrient sensitivity in LepRArc neurons.
“Together these data demonstrate that leptin action on reducing T1D hyperglycemia is mediated through reversing energy deprivation in LepRArc neurons, leading to inhibition of these neurons, and reduced counter-regulatory responses,” the authors said. “Thus, understanding the mechanism underlying leptin action on reversal in energy deprivation is imperative for a full understanding of T1D pathogenesis and more efficient treatment strategies against T1D.”
Shengjie Fan, PhD, postdoctoral research fellow; and Yuanzhong Xu, PhD, research instructor; mainly contributed to the work with help from other members in the Tong lab. Collaborators Ben Arenkiel, PhD; Mingshan Xue, PhD; Qi Wu, PhD; and Yong Xu, MD, PhD; from Baylor College of Medicine provided key reagents for the study.